# Pathogenic Mechanisms of Vascular Dysfunction in Scrub Typhus

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $395,000

## Abstract

Scrub typhus is a life-threatening disease caused by Orientia tsutsugamushi, a LPS-negative bacterium that
replicates preferentially in endothelial cells (EC) and phagocytes. While one million people are infected yearly,
with about one-third of world population at risk of infection, effective strategies for infection control are lacking.
Information on disease pathogenesis and immune dysregulation is limited. To address these challenges, we
have developed mouse models that mimic certain key pathological features of human scrub typhus. We found
that endogenous damage-associated molecular pattern (DAMP) molecules such as HMGB1 and
myeloperoxidase (MPO) are key regulators responsible for molecular dysfunctions involving angiopoietin 2
(Ang2), Tie2, and CD41+ platelets. We also discovered the detrimental effect of sustained neutrophil activation
in thrombocytopenia and vascular injury, and the potential of Ang2 and miR-200b as unique biomarkers for
vascular dysfunction. The objective of this study is to define pathogenic mechanisms of vascular dysfunction
and therapeutic modalities for severe scrub typhus by utilizing the EC-targeting model of O. tsutsugamushi
infection. Our central hypothesis is that the infection-triggered release of DAMPs exacerbates O.
tsutsugamushi-induced vascular damage by altering neutrophil/platelet activation; interventions aimed at
preserving vascular integrity or phagocyte function help to elicit a balanced immunity against acute tissue
damage and severe scrub typhus. This hypothesis will be tested in three cohesive Specific Aims. Aim 1 will
examine the mechanisms of HMGB1- and TNF-mediated sensitization and exacerbation of human
endothelium in Orientia infection. We will use human microvascular endothelial cells (HMEC) to test whether
Orientia triggers the release of HMGB1, TNF, Ang2, and miR-200b and their target genes/proteins, and if
therapeutics targeting these mechanisms mitigate EC injury. Aim 2 will examine mechanisms by which
neutrophils and HMGB1 contribute to vascular and platelet dysfunction during infection in mice. We will set up
lethal and sublethal infections in CXCR2-/- or MPO-/- mice at different infection stages. Likewise, the deletion of
RAGE (a HMGB1 receptor, RAGE-/- mice) or anti-RAGE antibody will reveal specific roles of HMGB1/RAGE
signaling in tissue-infiltrated leukocytes, platelet and vascular function. Aim 3 will test whether anti-Ang2 and
statin-based therapeutics promote host survival via modulating vascular function and phagocyte activation in
mice. Mice will be treated with anti-Ang2 antibody, recombinant Ang1, or statins (alone or in combination)
before or during lethal and sublethal infection. We will examine bacterial dissemination, neutrophil/platelet
activation, and the levels of Tie2 and signature cytokines/DAMPs. This mechanism-focused study capitalizes
on the synergism among several research teams. Discovery of vascular-specific biomarkers, novel regulatory
pathways, and their im...

## Key facts

- **NIH application ID:** 9982174
- **Project number:** 5R01AI132674-03
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** LYNN SOONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2018-08-02 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982174

## Citation

> US National Institutes of Health, RePORTER application 9982174, Pathogenic Mechanisms of Vascular Dysfunction in Scrub Typhus (5R01AI132674-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982174. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*